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1.
Angew Chem Int Ed Engl ; 57(44): 14560-14565, 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30212610

RESUMO

The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate-derived sulfinimine provides rapid access into a variety of enantiomerically pure α-amino acids (>85 examples). Characterized by operational simplicity, this radical-based reaction enables the modular assembly of exotic α-amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high-throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns.

2.
J Am Chem Soc ; 140(32): 10363-10367, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30029574

RESUMO

An acetyl-protected aminoethyl phenyl thioether has been developed to promote C(sp3)-H activation. Significant ligand enhancement is demonstrated by the realization of the first Pd(II)-catalyzed olefination of C(sp3)-H bonds of free carboxylic acids without using an auxiliary. Subsequent lactonization of the olefinated product via 1,4 addition provided exclusively monoselectivity in the presence of multiple ß-C-H bonds. The product γ-lactone can be readily opened to give either the highly valuable ß-olefinated or γ-hydroxylated aliphatic acids. Considering the challenges in developing Heck couplings using alkyl halides, this reaction offers a useful alternative.

3.
Nat Chem ; 10(2): 205-211, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29359756

RESUMO

The advent of antibody-drug conjugates as pharmaceuticals has fuelled a need for reliable methods of site-selective protein modification that furnish homogeneous adducts. Although bioorthogonal methods that use engineered amino acids often provide an elegant solution to the question of selective functionalization, achieving homogeneity using native amino acids remains a challenge. Here, we explore visible-light-mediated single-electron transfer as a mechanism towards enabling site- and chemoselective bioconjugation. Specifically, we demonstrate the use of photoredox catalysis as a platform to selectivity wherein the discrepancy in oxidation potentials between internal versus C-terminal carboxylates can be exploited towards obtaining C-terminal functionalization exclusively. This oxidation potential-gated technology is amenable to endogenous peptides and has been successfully demonstrated on the protein insulin. As a fundamentally new approach to bioconjugation this methodology provides a blueprint toward the development of photoredox catalysis as a generic platform to target other redox-active side chains for native conjugation.

4.
Nature ; 551(7681): 489-493, 2017 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-29168802

RESUMO

The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.


Assuntos
Carbono/química , Hidrocarbonetos Aromáticos/química , Hidrogênio/química , Piridonas/química , Alcenos/química , Produtos Biológicos/química , Catálise , Ligantes , Paládio/química , Preparações Farmacêuticas/química
5.
Org Lett ; 19(22): 6196-6199, 2017 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-29115835

RESUMO

Tetrachloro-N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (CITU) is disclosed as a convenient and economical reagent for both acylation and decarboxylative cross-coupling chemistries. Within the former set of reactions, CITU displays reactivity similar to that of common coupling reagents, but with increased safety and reduced cost. Within the latter, increased yields, more rapid conversion, and a simplified procedure are possible across a range of reported decarboxylative transformations.


Assuntos
Peptídeos/química , Acilação , Indicadores e Reagentes , Estrutura Molecular
6.
Bioorg Med Chem Lett ; 27(21): 4908-4913, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28947151

RESUMO

The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.


Assuntos
Desenho de Drogas , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Niacinamida/química , Inibidores de Proteínas Quinases/química , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Janus Quinase 3/química , Janus Quinase 3/metabolismo , Conformação Molecular , Simulação de Dinâmica Molecular , Niacinamida/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
7.
Angew Chem Int Ed Engl ; 56(36): 10924-10927, 2017 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-28714148

RESUMO

The palladium(II)-catalyzed C(sp3 )-H alkynylation of oligopeptides was developed with tetrabutylammonium acetate as a key additive. Through molecular design, the acetylene motif served as a linchpin to introduce a broad range of carbonyl-containing pharmacophores onto oligopeptides, thus providing a chemical tool for the synthesis and modification of novel oligopeptide-pharmacophore conjugates by C-H functionalization. Dipeptide conjugates with coprostanol and estradiol were synthesized by this method for potential application in targeted drug delivery to tumor cells with overexpressed nuclear hormone receptors.

8.
Science ; 355(6324): 499-503, 2017 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-28154075

RESUMO

The enzymatic ß-C-H hydroxylation of the feedstock chemical isobutyric acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transition metal-catalyzed enantioselective ß-C-H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge. Herein, we report the design of chiral mono-protected aminomethyl oxazoline ligands that enable desymmetrization of isopropyl groups via palladium insertion into the C(sp3)-H bonds of one of the prochiral methyl groups. We detail the enantioselective ß-arylation, -alkenylation, and -alkynylation of isobutyric acid/2-aminoisobutyric acid derivatives, which may serve as a platform for the construction of α-chiral centers.

9.
Bioorg Med Chem Lett ; 27(4): 855-861, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28108251

RESUMO

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.


Assuntos
Aminas/química , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Aminas/metabolismo , Aminas/uso terapêutico , Animais , Doenças Autoimunes/tratamento farmacológico , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Piperazina , Piperazinas/química , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Relação Estrutura-Atividade , Triazinas/química
10.
Angew Chem Int Ed Engl ; 56(3): 728-732, 2017 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-27860140

RESUMO

A method for the decarboxylative macrocyclization of peptides bearing N-terminal Michael acceptors has been developed. This synthetic method enables the efficient synthesis of cyclic peptides containing γ-amino acids and is tolerant of functionalities present in both natural and non-proteinogenic amino acids. Linear precursors ranging from 3 to 15 amino acids cyclize effectively under this photoredox method. To demonstrate the preparative utility of this method in the context of bioactive molecules, we synthesized COR-005, a somatostatin analogue that is currently in clinical trials.


Assuntos
Peptídeos/síntese química , Catálise , Ciclização , Descarboxilação , Substâncias Macromoleculares/síntese química , Substâncias Macromoleculares/química , Estrutura Molecular , Oxirredução , Peptídeos/química , Processos Fotoquímicos
11.
J Org Chem ; 81(19): 9499-9506, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27615449

RESUMO

A one-step synthesis of Fmoc-protected aryl/heteroaryl-substituted phenylalanines (Bip derivatives) using the nonaqueous palladium-catalyzed Suzuki-Miyaura cross-coupling (SMC) reaction of Fmoc-protected bromo- or iodophenylalanines is reported. This protocol allows for the direct formation of a variety of unnatural biaryl-containing amino acids in good to excellent yield, which can be readily used in subsequent Fmoc solid-phase peptide synthesis. The synthetic utility of this method is also demonstrated by the SMC reaction of bromophenylalanine-containing tripeptides.

12.
Bioorg Med Chem Lett ; 26(17): 4256-60, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27476421

RESUMO

Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.


Assuntos
Aminas/química , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Triazinas/química , Aminas/metabolismo , Aminas/uso terapêutico , Animais , Artrite/tratamento farmacológico , Artrite/metabolismo , Artrite/patologia , Sítios de Ligação , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Camundongos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Relação Estrutura-Atividade
13.
J Med Chem ; 58(22): 9010-26, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26524347

RESUMO

Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.


Assuntos
Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Benzilaminas/síntese química , Benzilaminas/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Animais , Anticolesterolemiantes/farmacocinética , Aterosclerose/tratamento farmacológico , Benzamidas/farmacocinética , Benzilaminas/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Linhagem Celular , Colesterol/metabolismo , HDL-Colesterol/sangue , Cricetinae , Citocromo P-450 CYP11B2/antagonistas & inibidores , Cães , Descoberta de Drogas , Humanos , Macaca fascicularis , Masculino , Mesocricetus , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley
14.
J Am Chem Soc ; 137(9): 3338-51, 2015 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-25697780

RESUMO

Pd-catalyzed ß-C-H functionalizations of carboxylic acid derivatives using an auxiliary as a directing group have been extensively explored in the past decade. In comparison to the most widely used auxiliaries in asymmetric synthesis, the simplicity and practicality of the auxiliaries developed for C-H activation remains to be improved. We previously developed a simple N-methoxyamide auxiliary to direct ß-C-H activation, albeit this system was not compatible with carboxylic acids containing α-hydrogen atoms. Herein we report the development of a pyridine-type ligand that overcomes this limitation of the N-methoxyamide auxiliary, leading to a significant improvement of ß-arylation of carboxylic acid derivatives, especially α-amino acids. The arylation using this practical auxiliary is applied to the gram-scale syntheses of unnatural amino acids, bioactive molecules, and chiral bis(oxazoline) ligands.


Assuntos
Aminoácidos/química , Alanina/química , Aminoácidos/síntese química , Ácidos Carboxílicos/química , Catálise , Técnicas de Química Sintética , Hidrogênio/química , Ligantes , Paládio/química , Fenilalanina/química , Piridinas
15.
Bioorg Med Chem Lett ; 23(14): 4107-11, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23747226

RESUMO

The design, synthesis and characterization of a phosphonate inhibitor of N-acetylneuraminate-9-phosphate phosphatase (HDHD4) is described. Compound 3, where the substrate C-9 oxygen was replaced with a nonlabile CH2 group, inhibits HDHD4 with a binding affinity (IC50 11µM) in the range of the native substrate Neu5Ac-9-P (compound 1, Km 47µM). Combined SAR, modeling and NMR studies are consistent with the phosphonate group in inhibitor 3 forming a stable complex with native Mg(2+). In addition to this key interaction, the C-1 carboxylate of the sugar interacts with a cluster of basic residues, K141, R104 and R72. Comparative NMR studies of compounds 3 and 1 with Ca(2+) and Mg(2+) are indicative of a highly dynamic process in the active site for the HDHD4/Mg(2+)/3 complex. Possible explanations for this observation are discussed.


Assuntos
Desenho de Drogas , Inibidores Enzimáticos/síntese química , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Ácidos Siálicos/síntese química , Fosfatos Açúcares/síntese química , Animais , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Cinética , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Monoéster Fosfórico Hidrolases/metabolismo , Estrutura Terciária de Proteína , Ratos , Ácidos Siálicos/química , Ácidos Siálicos/metabolismo , Fosfatos Açúcares/química , Fosfatos Açúcares/metabolismo
16.
J Med Chem ; 56(4): 1704-14, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23368907

RESUMO

Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP-driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that P2Y1 and P2Y12 inhibition provide equivalent antithrombotic efficacy, while targeting P2Y1 has the potential for reduced bleeding liability. In this account, the discovery of a 2-(phenoxypyridine)-3-phenylurea chemotype that inhibited ADP-mediated platelet aggregation in human blood samples is described. Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-4-(trifluoromethoxy)phenylurea, which demonstrated a 68 ± 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively, in provoked rat bleeding time models. These results suggest that a P2Y1 antagonist could potentially provide a safe and efficacious antithrombotic profile.


Assuntos
Fibrinolíticos/síntese química , Compostos de Fenilureia/síntese química , Antagonistas do Receptor Purinérgico P2Y/síntese química , Piridinas/síntese química , Ureia/análogos & derivados , Animais , Arteriopatias Oclusivas/sangue , Arteriopatias Oclusivas/tratamento farmacológico , Tempo de Sangramento , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Células HEK293 , Humanos , Masculino , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade , Trombose/sangue , Trombose/tratamento farmacológico , Ureia/síntese química , Ureia/química , Ureia/farmacologia
17.
J Med Chem ; 55(21): 9208-23, 2012 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-23030502

RESUMO

This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-π interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma Aß levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain Aß levels were not obtained.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Guanidinas/síntese química , Bibliotecas de Moléculas Pequenas , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/química , Encéfalo/metabolismo , Linhagem Celular , Cristalografia por Raios X , Guanidinas/farmacocinética , Guanidinas/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Modelos Moleculares , Estrutura Molecular , Mutação , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Ensaio Radioligante , Ratos , Técnicas de Síntese em Fase Sólida , Soluções , Relação Estrutura-Atividade
19.
J Med Chem ; 55(13): 6162-75, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22650305

RESUMO

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.


Assuntos
Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Estilbenos/química , Estilbenos/farmacologia , Animais , Anticolesterolemiantes/síntese química , Apolipoproteína B-100/antagonistas & inibidores , Apolipoproteína B-100/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Doença das Coronárias/tratamento farmacológico , Cricetinae , Descoberta de Drogas , Frequência Cardíaca/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Piridinas/síntese química , Ratos , Estilbenos/síntese química
20.
Bioorg Med Chem Lett ; 22(8): 2866-71, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22424979

RESUMO

Presented here are initial structure-activity relationship (SAR) studies on a series of novel heteroaryl fused tetracyclic indole-based inhibitors of the hepatitis C viral polymerase, NS5B. The introduction of alternative heterocyclic moieties into the indolo-fused inhibitor class significantly expands the reported SAR and resulted in the identification of pyridino analogs, typified by compounds 44 and 45 that displayed excellent potency against the NS5B polymerase of both HCV 1a and HCV 1b genotypes.


Assuntos
Amidas/química , Hepacivirus/efeitos dos fármacos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Amidas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Indóis/química , Indóis/farmacologia , Concentração Inibidora 50 , Relação Estrutura-Atividade
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